Surface-based ammonium ion sensor and methods of making thereof

ABSTRACT

A compound sensitive to and selective for ammonium ions over other ions. A sensor fabricated from a self assembled monolayer of said compound on gold, exhibiting sensitivity and selectivity for ammonium ions over other ions in aqueous solutions, including blood. A method of preparation of said compound and said sensor.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a U.S. national stage application under 35 U.S.C.371 of International Application No. PCT/US/78005 filed Sep. 10, 2007and entitled SURFACE-BASED AMMONIUM ION SENSOR: AN ELECTRODE DERIVATIZEDWITH A SELF-ASSEMBLED MONOLAYER, which in turn claims priority to U.S.Provisional Patent Application No. 60/843,351 filed Sep. 8, 2006.

CROSS REFERENCE TO RELATED APPLICATIONS

The present application is being filed under 35 U.S.C. §371 ofInternational Application No. PCT/US2007/078005, filed on Sep. 10, 2007,which claims priority to U.S. Provisional Application Ser. No.60/843,351, entitled A SURFACE-BASED AMMONIUM ION SENSOR: AN ELECTRODEDERIVATIZED WITH A SELF-ASSEMBLED MONOLAYER, filed on Sep. 8, 2006.

BACKGROUND OF THE INVENTION

Metabolite levels such as the amount of urea and creatinine in blood areimportant disease indicators. Urea and creatinine levels are measuredindirectly using enzyme-catalyzed hydrolysis to produce ammonium ions.Much work has focused on fabricating sensors for selective ammonium iondetection. In clinical use, the measurement of ammonium ionconcentrations is achieved by carrier-based ion selective electrodes(ISEs) containing an ionophore, a ligand which has high selectivity andsensitivity to specific ions. The natural antibiotic nonactin is themost widely studied compound used as an ammonium ionophore. However,nonactin-based ammonium ISEs have a limit in their utility due to thepoor selectivity of ammonium over potassium ions (log K_(NH4) ⁺ _(,K)⁺˜−0.9).

Modification of gold surfaces with self-assembled monolayers (SAMs) oforganic compounds has received considerable interest due to thepotential application of such as microfluidic sensors. The introductionof a selective ionophore in the adsorbates allows the development ofrapidly responding chemical sensors. The use of SAMs in sensortechnology has typically used electrochemical techniques to transducethe binding of the analyte. Cyclic voltammetry (CV) and impedancespectroscopy (IS) techniques allow the detection of metal cationcomplexation by the monolayer by measuring changes in conductivity orcapacitance. There are reports in the literature of the preparation ofSAMs of alkanethiols bearing crown-ethers that can complexnon-electrochemically active ions such as Na⁺ and K⁺, ormetallosalophenes that complex transition metal ions (e.g. Ni²⁺, Cu²⁺and Co²⁺), whereby the binding processes were studied utilizing CV andimpedance techniques. Also there are reports of the studies of ionrecognition properties of other molecules on gold, such as helicalpeptides linked to a crown ether, crown ethers bonded totetrathiafulvalene disulfides, and alkanethiols modified withnitrilotriacetic acid.

In our previous work an ammonium ionophore based on a cyclicdepsi-peptide structure was incorporated into a planar ion-selectiveelectrode (ISE) sensor format, which provides selectivity for NH₄ ⁺against the interfering ions, Na⁺, and K⁺, log K_(NH4) ⁺ _(,Na) ⁺˜−2.1and log K_(NH4) ⁺ _(,K) ⁺˜−0.6. However the electrode requiresubstantial amount of ionophore for fabrication and exhibits longequilibration times, which limits its practical applications.

SUMMARY OF THE INVENTION

The present invention relates to a NH₄ ⁺ sensor fabricated from a selfassembled monolayer on gold. This sensor is characterized by small size,requires minimum amounts of ionophore material for fabrication andexhibits extremely fast equilibration times. The sensor can be used inaqueous environments. Accordingly, the ionophore moiety was synthesizesuch that it can attach to the gold surface in order to monitor atransduction mechanism in aqueous media. In one embodiment of thisinvention monolayers of hexadecanethiol coupled to a cyclic depsipetidemolecule with the ability to selectively complex NH₄ ⁺ ions werefabricated. The ability of these monolayers to function as sensors wasshown by impedance spectroscopy. Impedance experiments in the absence ofa redox probe (i.e. only supporting electrolyte) provided reproducibledata that shows a change in monolayer capacitance upon ion complexation.The compound showed selectivity for complexation of NH₄ ⁺ ions overother ions, with log K_(NH4) ⁺ _(,Na) ⁺˜−1.23 and log K_(NH4) ⁺ _(,K)⁺˜−1.17. This selectivity differs from the selectively of the samecompound in an ISE membrane. This selectivity over potassium ions issuperior to that obtained for an ionophore of this compound in an ISEmembrane (log K_(NH4) ⁺ _(,K) ⁺˜−0.6), although it is somewhat lessselectivity for sodium ions (log K_(NH4) ⁺ _(,Na)+˜−2.1.) This studyshows that selective ion complexation can be demonstrated on surfacesusing an impedance measurement technique.

For a better understanding of the present invention, together with otherand further objects thereof, reference is made to the accompanyingdrawings and detailed description. The scope of the present invention ispointed out in the appended claims.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a pictorial diagram of an illustrative structure of the NH₄ ⁺sensor on gold surface;

FIG. 2A is a pictorial diagram of an illustrative scheme 1 for thesyntheses of block 1 and block 3 in the synthetic sequence that leads tothe synthesis of compound I;

FIG. 2B is a pictorial diagram of an illustrative synthetic scheme 2 forthe synthesis of block 2 in the synthetic sequence that leads to thesynthesis of compound I;

FIG. 2C is a pictorial diagram of an illustrative synthetic scheme 3 inthe synthetic sequence that leads to the synthesis of compound I;

FIG. 3 is a grazing angle FT-IR spectrum of compound I on gold;

FIG. 4 is a graph of Nyquist plots obtained at −0.5 V vs Ag/AgCl with asupporting electrolyte solution of (1) 0 mM NH₄Cl and 0.1 M tetraethylammonium bromide and (2) 20 mM NH₄Cl and 0.08 M tetraethyl ammoniumbromide, wherein the inset illustrates the equivalent circuit used tofit the spectra in this study, containing an electrolyte resistance(REL), a monolayer capacitance (CML), a charge-transfer resistance(RCT), and a diffusion element (W);

FIG. 5 is a graph of the capacitance of compound I on gold as a functionof ion concentration for different ions; and

FIG. 6 is a pictorial diagram of the structure of the ionophore ofcompound I.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

The present invention is now described more fully hereinafter withreference to the accompanying drawings, in which the illustrativeembodiments of the present invention are shown.

The SAM comprises a single molecular layer of a cyclic depsi-peptidestructure shown in FIG. 1. The compound shown in FIG. 1 is a11-mercapto-N-(4-(9,15,18-triisopropyl-6,12-dimethyl-2,5,8,11,14,17-hexaoxo-1,7,13-trioxa-4,10,16-triazacyclooctadecan-3-yl)butyl)undecanamide, comprising an alkanethiol moiety and a cyclicdepsi-peptide moiety. Alkanethiol moiety was used to form a relativelywell ordered self-assembled monolayer on gold, with the cyclicdepsi-peptide moiety exposed on the surface. This compound was designedfollowing a similar approach that was used for our previously reportedionophores and fluoroionophores. See, Benco, J. S., Nienaber, H. A.,McGimpsey, W. G. Anal. Chem., 75, p 152-156 (2003); Benco, J. S.,Nienaber, H. A., Dennen, K., McGimpsey, W. G. J. Photochem. Photobiol.,A., 152, p 33-40 (2002); Benco, J. S., Nienaber, H. A., Grant McGimpsey,W. Sens. Actuators, B., B85, p 126-130 (2002); Benco, J. S.; Nienaber,H. A.; McGimpsey, W. G. J. Photochem. Photobiol., A., 162, p 289-296(2004); and Wanichecheva, N., Benco, J. S., Lambert, C. R., McGimpsey,W. G. Photochem. Photobiol, 82, p 268-273 (2006), the entire teachingsof which are incorporated herein by reference. Molecular modeling of thecyclic structure showed that it provides a rigid framework and size fitfor an ammonium ion. The ammonium ion binding ability of thesurface-bound sensor was monitored by cyclic voltammetry and impedancespectroscopy. Formation of a monolayer on gold was monitored by contactangle, ellipsometry and FT-IR.

Contact angle showed the formation of a slightly hydrophobic layer(46±2°) compared to bare gold (13±2°), and ellipsometry demonstrates theformation of a single layer on the surface (layer thickness: 2.8±0.3nm). The best evidence of deposition of compound I on gold comes fromgrazing-incidence infrared spectroscopy (see FIG. 3.) The grazing angleFT-IR spectrum of I on gold shows an absorption peak at 1741 and 1673cm⁻¹ corresponding to the carbonyl group of the ester bonds and amidebonds, respectively. An absorption peak at 1435 cm⁻¹ shows the C—Nbonds. An absorption peak at 1114 cm⁻¹ shows the C—O bonds. Othersignificant bands in the IR spectra are the methylene stretchingvibrations at 2969 and 2933 cm⁻¹. The broad band at 3234 cm⁻¹ shows thehydrogen bonding.

The analysis of the SAM based sensor was carried out using impedancetechniques to show the ability of the SAM to bind NH₄ ⁺ ionsselectively. Experiments were conducted in the presence of a backgroundelectrolyte solution of 0.1 M tetraethylammonium chloride at a constantpotential of −0.5 V vs a Ag/AgCl reference electrode at differentconcentrations of NH₄ ⁺, K⁺, Na⁺ or Li⁺. The experimental Nyquist plotscan then be fit to a model circuit, in this case a Randles equivalentcircuit, using non-linear least squares fitting. A Randles circuitconsists of a solution resistance in series with the parallelcapacitance and resistance of the monolayer. A Warburg element is due tothe diffusion limitation at low frequencies. The inset shown in FIG. 4is the equivalent circuit used to fit the spectra in this study. Thecapacitance of the monolayer-covered electrode, C_(ML), is proportionalto the dielectric constant of the monolayer as shown in the followingexpression:C _(ML)=∈₀∈_(r) A/dwhere ∈₀ is the permittivity of vacuum, ∈_(r) is the dielectric constantof the monolayer, A is the surface area and d is the average layerthickness. The capacitance of the monolayer will change in relation tothe degree of ion binding because of the increase in the dielectricconstant of the film as more metal ions are complexed. Nyquist plotsobtained at two different concentrations of NH₄ ⁺ ions are shown in FIG.4. Fitting this data to the previously described equivalent circuitgives capacitance values for the monolayer that are related to metal ionconcentration. A plot of capacitance changes vs ion concentration isshown in FIG. 5. The capacitance results show that the SAMs have a loweraffinity for Na⁺ and K⁺. The complexation of NH₄ ⁺ and ionophore I (seeFIG. 6) on gold surface was studied to provide evidence that thesupporting electrolyte (tetrabutyl ammonium bromide or tetraethylammonium chloride) does not significantly interfere in the impedancemeasurements. The molecular modeling of ionophore I in water usingforcefields AMBER94 and MMFF94 showed unstable complexes of ionophore Ito tetraethyl ammonium ion. The results show that the capacitanceincreases as a function of ion concentration until it reaches a plateau,beyond which it is constant up to the maximum concentration tested (0.1M). FIG. 5 demonstrates that SAMs of this sensor provide selectivity forammonium ions over potassium and sodium ions with log K_(NH4) ⁺ _(,Na)⁺˜−1.23 and log K_(NH4) ⁺ _(,K) ⁺˜−1.17. Selectivity was calculated by amethod used in ion selective electrode applications (see, Bakker, E.,Buehlmann, P., Pretsch, E., Chem. Rev., 97, p 3083-3132 (1997), theentire teaching of which is incorporated herein by reference.)Selectivity is represented as a logarithmic value and is calculatedusing the following equation:log K _(i,j)=log([i]/[j])Here, [j] is the concentration of the interfering ion in the plateauregion of the plot, where the concentration of the interfering ionprovides the maximum capacitance response. The concentration of theprimary ion, [i], is the concentration that gives the same response asthe maximum capacitance produce by the interfering ion, representing aminimum unambiguous detection limit for the primary ion.

The ionophore of compound I has also been used as an ionophore for ionselective electrode format (see FIG. 6.) This ionophore inpolyvinylchloride (PVC) membrane provides selectivity for ammonium ionsover potassium and sodium ions with log K_(NH4) ⁺ _(,Na) ⁺˜−2.1 and logK_(NH4) ⁺ _(,K) ⁺˜−0.6. It is noteworthy that this ionophore appears toexhibit different selectivity in the different formats which hasimplications for the fabrication of a SAM based on ion selectiveelectrode.

EXAMPLES

All reagents and solvents for synthesis were purchased from AldrichChemical (Milwaukee, Wis.), unless otherwise noted. D-Hydroxyisovalericacid was purchased from Fluka Chemical Corporation (Milwaukee, Wis.).L-Lactic acid was purchased from Alfa Aesar. Amino acids and couplingreagents, Boc-D-Val-OH, Boc-Lys(Fmoc)-OH,benzotriazole-1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophos phate(PyBOP), and 1-hydroxybenzo-triazole hydrate (HOBT), were purchased fromCalbiochem-Novabiochem Corp. (San Diego, Calif.). Electrolyte solutionswere freshly prepared using high-purity Millipore deionized water (18MΩ.cm).

NMR spectra were obtained in an Avance Bruker spectrometer at 400 MHzfor proton and 100 MHz for ¹³C NMR spectra were obtained in CDCl₃ orMeOD solutions. Mass spectra were measured by SynPep Corporation(Dublin, Calif.) or Water Micromass Model ZMD, Mass Spectrometer.Ionization was performed using electrospray, with an aqueous solution ofacetonitrile or methanol as the carrier solvent, and nitrogen as acurtain gas. Melting point data was obtained using a MeI-Temp capillarymelting point apparatus and were not corrected.

Example 1 Synthesis of11-mercapto-N-(4-(9,15,18-triisopropyl-6,12-dimethyl-2,5,8,11,14,17-hexaoxo-1,7,13-trioxa-4,10,16-triazacyclooctadecan-3-yl)butyl)undecanamide (Compound I)

The synthetic schemes for target compound I are shown in FIG. 2A-C.Three building blocks were synthesized from the correspondingbenzyl-L-lactic acid and Boc-D-Val-OH residue (block 1),D-Hydroxyisovaleric acid and Boc-Lys(Fmoc)-OH residue (block 2),L-lactic acid and Boc-D-Val-OH residue (block 3). These building blockswere coupled sequentially as block 1-block 2-block 3, then cyclized togive cyclic depsipeptide, and finally coupled with 11-mercaptoundecanoicacid to give the title compound I. All of the ester and amide bonds ofthe depsi-peptide were created in solution. Three types of protectinggroups, (t-Butyl (tBu), fluorenylmethoxycarbonyl (Fmoc), and benzyloxy(BzlO)) were used in this synthesis strategy.

Following is the description of the synthetic scheme 1 presented in FIG.2A.

(i) Benzyl Ester L-Lactic Acid, (BzlO-L-Lac)

In a round bottom flask, 25.00 g (277.53 mmol) of L-lactic acid wasdissolved in 300 mL of anhydrous benzyl alcohol. The solution wassaturated with HCl gas and stirred for 18 hrs. at room temperature whereupon the solution was dilute with 400 mL CH₂Cl₂. The organic layer waswashed 3 times with 200 mL 1N KOH, and then with 200 mL 10% citric acidand dried over Na₂SO₄. The CH₂Cl₂ fraction was then removed undervacuum, 40° C. The benzyl alcohol was removed by vacuum distillation at35° C. (2.5 mmHg) and the product was collected at 60° C. as a colorlessoil, 33.11 g, 66.20% yield. The NMR spectra confirms to the literature(see, Borchardt, M., Dumschat, C., Cammann, K., Knoll, M., Sens.Actuators, B., B25, p 721-723 (1995.) ¹H-NMR (400 MHz, CDCl₃), δ 1.42(dd, J=7.07, 1.01, 3H), 3.08 (d, J=4.80, 1OH), 4.28-4.34 (m, 1H), 5.19(s, 2H), 7.30-7.38 (m, 5H); ¹³C-NMR (100 MHz, CDCl₃), δ 20.5 (CH₃), 67.0(CH), 67.3 (CH₂), 127.9, 128.4, 128.6, 128.8 (CH—Ar), 135.4 (C—Ar),175.7 (C═O).

(ii) BzlO-L-Lac-D-Val-NHboc (Block 1)

In a round bottom flask, 10.00 g (46.01 mmol) of Boc-D-Val-OH wasdissolved in 200 mL of anhydrous CH₂Cl₂. The solution was stirred for 15min at 0° C., then 7.12 mL (1 eq.) of diisopropylcarbodiimide (DIPCDI)was added followed by adding 0.56 g (0.1 eq.) of 4-dimethylaminopyridine(DMAP). The solution was stirred for 15 min. in ice bath where upon 8.29g (1 eq.) of L-lactic acid benzyl ester was added. After the solutionwas stirred at 0° C. for 1 hr, it was then stirred for an additional 17hrs. at room temperature. The insoluble urea thus formed was filteredoff, then the solution was washed thrice with 200 mL saturated NaHCO₃,thrice with 200 mL 10% citric acid, once with water and then dried overNa₂SO₄. The CH₂Cl₂ fraction was then removed under vacuum, 45° C. toyield a clear gum. The product was obtained by column chromatography(hexane: EtOAc: CH₂Cl₂ 9:1:1) to yield 16.48 g of a colorless oil, yield94.39%. R_(f)=0.29 (hexane: EtOAc: CH₂Cl₂ 9:1:1); ¹H-NMR (400 MHz,CDCl₃), δ 0.90 (d, J=7.07, 3H), 0.97 (d, J=7.07, 3H), 1.43-1.47 (m, 9H),1.51 (d, J=7.07, 3H), 2.06-2.09 (m, 1H), 4.27-4.35 (m, 1H), 5.03 (q,J=8.84, 1H), 5.15-5.20 (m, 2H), 7.30-7.40 (m, 5H); ¹³C-NMR (100 MHz,CDCl₃), δ 17.1 (CH₃), 17.6 (CH₃), 19.1 (CH₃), 28.4 (3×CH₃), 31.4 (CH),58.7 (CH), 67.2 (CH₂), 69.3 (CH), 79.8 (C), 128.3, 128.6, 128.7 (CH—Ar)135.3 (C—Ar), 155.7, 170.2, 171.6 (C═O).

(iii) L-Lac-D-Val-NHboc, (Block 3)

In a round bottom flask, 6.00 g (15.81 mmol) of theBzlO-L-Lac-D-Val-NHboc was dissolved in 100 mL anhydrous CH₂Cl₂. Thebenzyl ester group was removed by hydrogenation reaction using 0.50 g ofPd activated carbon as the catalyst, and gas hydrogen (H₂) flowed overfor 4 hrs. Then the Pd activated carbon was filtered off and thesolution was concentrated under vacuum, 45° C., to yield a light-yellowgum. The product was obtained by column chromatography, the column beinga normal phase silica gel column having a particle size of 40 micronsand a pore size of 60 Angstroms (hereinafter “column chromatograph”),(CH₂Cl₂:MeOH 85:15) to yield 4.11 g of a white amorphous solid, yield89.93%. R_(f)=0.4 (CH₂Cl₂:MeOH 85:15); ¹H-NMR (400 MHz, CD₃OD), δ 0.96(d, J=7.07, 3H), 1.00 (d, J=7.07, 3H), 1.43-1.51 (m, 12H), 2.11-2.22 (m,1H), 4.10 (d, J=5.81, 1H), 5.05-5.10 (m, 1H); ¹³C-NMR (100 MHz, CD₃OD),δ 16.5 (CH₃), 17.4 (CH₃), 18.6 (CH₃), 27.6 (CH₃), 27.8 (2×CH₃), 30.9(CH), 59.7 (CH), 69.4 (CH), 79.6 (C), 157.2, 172.1, 172.8 (C═O).

Following is the description of the synthetic scheme 2 presented in FIG.2B.

(i) D-hydroxyisovaleric acid benzyl ester. (BzlO-D-Hyisoval)

This compound was prepared in the same manner as L-lactic acid benzylester using 9.80 g (82.96 mmol) of D-hydroxyisovaleric acid. The productwas recovered as a colorless oil, 10.12 g, 58.58% yield. The NMR spectraconfirms to the literature (see, Liu, D., Meyerhoff, M. E., Goldberg, H.D., Brown, R. B., Anal. Chim. Acta., 274, p 37-46 (1993); Pranitis, D.M., Meyerhoff, M. E., Anal. Chem., 59, 2345-2350 (1987.) ¹H-NMR (400MHz, CDCl₃), δ 0.83 (d, J=7.07, 3H), 1.00 (d, J=7.07, 3H), 2.07-2.13 (m,1H), 2.76 (d, J=5.81, 1OH), 4.04-4.13 (m, 1H), 5.15-5.28 (m, 2H),7.25-7.51 (m, 5H); ¹³C-NMR (100 MHz, CDCl₃), δ 16.0 (CH₃), 19.0 (CH₃),32.3 (CH), 67.5 (CH₂), 75.2 (CH), 127.8, 128.0, 128.6, 128.7, 128.8(CH—Ar), 135.4 (C—Ar), 175.0 (C═O).

(ii) BzlO-D-Hyisoval-L-Lys(Fmoc)-NHboc.

In a round bottom flask, 10.00 g (21.34 mmol) of Boc-Lys(Fmoc)-OH wasdissolved in 200 mL of anhydrous CH₂Cl₂. The solution was stirred for 15min at 0° C., then 3.3 mL (1 eq.) of DIPCDI was added followed by adding0.26 g (0.1 eq.) of DMAP. The solution was stirred for 15 min. in icebath where upon 4.44 g (1 eq.) of BzlO-D-hyisoval was added. After thesolution was stirred at 0° C. for 1 hr, it was then stirred for anadditional 17 hrs. at room temperature. The insoluble urea thus formedwas filtered off, then the solution was washed thrice with 150 mLsaturated NaHCO₃, thrice with 150 mL 10% citric acid, once with waterand then dried over Na₂SO₄. The CH₂Cl₂ fraction was then removed undervacuum, 45° C. to yield a white amorphous crystal. The product waspurified by recrystallization using dichloromethane and cold ether toyield a white solid, and followed by column chromatography (hexane:EtOAc7:3) to yield 9.87 g of a white crystal, yield 70.20%. R_(f)=0.31(hexane:EtOAc 7:3); ¹H-NMR (400 MHz, CDCl₃), δ 0.93 (d, J=7.07, 3H),0.97 (d, J=7.07, 3H), 1.23-1.59 (m, 13H), 1.61-1.76 (m, 1H), 1.76-1.93(m, 1H), 2.19-2.33 (m, 1H), 2.94-3.27 (m, 2H), 4.17-4.25 (dd, J=7.07,6.82, 1H), 4.35-4.43 (m, 2H), 4.87-4.98 (m, 2H), 5.02-5.25 (m, 2H),7.25-7.45 (m, 9H), 7.59 (d, J=7.58, 2H), 7.75 (d, J=7.58, 2H); ¹³C-NMR(100 MHz, CDCl₃), δ 17.3 (CH₃), 19.0 (CH₃), 22.5 (CH₂), 28.5 (3×CH₃),29.5 (CH₂), 30.3 (CH), 32.4 (CH₂), 40.7 (CH₂), 47.4 (CH), 53.7 (CH),66.7 (CH₂), 67.2 (CH₂), 77.4 (CH), 80.3 (C), 120.1, 125.2, 127.2, 127.8,128.5, 128.6, 128.8 (CH—Ar), 135.4, 141.5, 144.2 (C—Ar), 155.5, 156.6,169.3, 172.3 (C═O).

(iii) D-Hyisoval-L-Lys(Fmoc)-NHboc (Block 2)

In a round bottom flask, 9.44 g (14.33 mmol) of theBzlO-D-hyisoval-L-Lys(Fmoc)-NHboc was dissolved in 200 mL anhydrousCH₂Cl₂. The benzyl ester group was removed by hydrogenation reactionusing 1 g of Pd activated carbon as the catalyst, and gas hydrogen (H₂)flowed over for 9 hrs. Then the Pd activated carbon was filtered off andthe solution was concentrated under vacuum, 45° C., to yield a whiteamorphous crystal. The product was obtained by column chromatography(CH₂Cl₂:MeOH 90:10) to yield 7.72 g of a white amorphous solid, yield94.74%. R_(f)=0.6 (90:10 CH₂Cl₂:MeOH); ¹H-NMR (400 MHz, CDCl₃), δ 0.99(d, J=7.07, 3H), 1.00 (d, J=7.07, 3H), 1.25-1.55 (m, 13H), 1.61-1.76 (m,1H), 1.76-1.95 (m, 1H), 2.19-2.35 (m, 1H), 2.92-3.25 (m, 2H), 4.11-4.25(m, 1H), 4.33-4.48 (m, 2H), 4.85-4.98 (m, 1H), 5.18-5.32 (m, 1H),7.24-7.42 (m, 4H), 7.57 (d, J=7.58, 2H), 7.74 (d, J=7.58, 2H), 10.0(s-br, 1H); ¹³C-NMR (100 MHz, CDCl₃), δ 17.1 (CH₃), 19.0 (CH₃), 22.5(CH₂), 28.3 (CH₃), 28.5 (2×CH₃), 29.5 (CH₂), 30.1 (CH), 32.1 (CH₂), 40.7(CH₂), 47.3 (CH), 53.6 (CH), 66.7 (CH₂), 77.4 (CH), 80.3 (C), 120.1,125.0, 125.2, 127.2, 127.8, 127.9 (CH—Ar), 141.4, 144.0 (C—Ar), 155.8,156.8, 172.4, 173.0 (C═O).

Following is the description of the synthetic scheme 3 presented in FIG.2C.

(i) BzlO-L-Lac-D-Val-NH₂

In a round bottom flask, 5.10 g (13.44 mmol) of block 1 was dissolved in50 mL anhydrous CH₂Cl₂, and then deprotected with 50% trifloroaceticacid (TFA, 50 mL) for 1 hr. The CH₂Cl₂ and TFA were then removed undervacuum, 35° C. 1 mL of CH₂Cl₂ and 2 mL of toluene were added thrice tothe residue, and then removed thrice under vacuum, to yield a brown gumresidue in quantitative yield. ¹H-NMR (400 MHz, CDCl₃), δ 1.02-1.10 (dd,J=7.07, 14.14, 6H), 1.50 (d, J=7.07, 3H), 2.30-2.41 (m, 1H), 3.96-4.02(d-br, J=3.03, 1H), 5.13 (q, J=8.84, 1H), 5.18-5.24 (m, 2H), 7.25-7.38(m, 5H); ¹³C-NMR (100 MHz, CDCl₃), δ 16.7 (CH₃), 17.5 (CH₃), 17.9 (CH₃),29.9 (CH), 58.4 (CH), 67.5 (CH₂), 70.5 (CH), 128.4, 128.5, 128.7, 128.7,129.2 (CH—Ar) 135.0 (C—Ar), 168.1, 169.7 (C═O).

(ii) BzlO-L-Lac-D-Val-D-Hyisoval-L-Lys(Fmoc)-NHboc

In a round bottom flask 7.60 g (13.36 mmol) ofD-hyisoval-L-Lys(Fmoc)-NHboc (block 2) was dissolved in 150 mL ofanhydrous CH₂Cl₂. The solution was stirred for 5 min at roomtemperature, then 6.96 g (1 eq.) ofbenzotriazole-1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate(PyBOP), 2.05 g (1 eq.) 1-hydroxybenzo-triazole hydrate (HOBT), and 23.3mL (10 eq.) of diisopropylethylamine (DIPEA) were added. The solutionwas stirred for 5 min. where upon the deprotecting block I in dry CH₂Cl₂was added. This solution mixture was then stirred for an additional 18hrs at room temperature. The insoluble urea thus formed was filteredoff, then the solution was washed thrice with 150 mL saturated NaHCO₃,thrice with 150 mL 10% citric acid, once with water and then dried overNa₂SO₄. The CH₂Cl₂ was then removed under vacuum, 45° C. to yield alight brown crystal. The product was purified by column chromatography(hexane:EtOAc 62:38) to yield 9.81 g of a white crystal, yield 88.44%.R_(f)=0.30 (hexane:EtOAc 62:38); ¹H-NMR (400 MHz, CDCl₃), δ 0.96-0.99(m, 12H), 1.26-1.52 (m, 16H), 1.62-1.78 (m, 1H), 1.78-1.93 (m, 1H),2.24-2.40 (m, 2H), 2.95-3.22 (m, 2H), 4.19 (m, 1H), 4.28 (m, 1H),4.33-4.42 (m, 2H), 4.52-4.60 (m, 1H), 5.04-5.21 (m, 5H), 5.32 (d,J=7.33, 1NH), 6.81 (d, J=8.08, 1NH), 7.26-7.35 (m, 7H), 7.38 (t, J=7.58,2H), 7.58 (d, J=7.58, 2H), 7.74 (d, J=7.58, 2H); ¹³C-NMR (100 MHz,CDCl₃), δ 16.9 (CH₃), 17.0 (CH₃), 18.1 (CH₃), 18.9 (CH₃), 19.1 (CH₃),22.6 (CH₂), 28.3 (3×CH₃), 29.5 (CH₂), 30.5 (CH), 30.8 (CH), 31.5 (CH₂),40.4 (CH₂), 47.3 (CH), 53.9 (CH), 57.5 (CH), 66.6 (CH₂), 67.2 (CH₂),69.4 (CH), 78.7 (C), 80.1 (CH), 120.0, 125.1, 127.1, 127.7, 128.2,128.5, 128.7, (CH—Ar), 135.2, 141.3, 144.0, 144.1 (C—Ar), 155.6, 156.7,169.2, 170.1, 170.7, 171.9 (C═O).

(iii) BzlO-L-Lac-D-Val-D-Hyisoval-L-Lys(Fmoc)-NH₂

In a round bottom flask, 9.30 g (11.20 mmol) of theBzlO-L-Lac-D-Val-D-hyisoval-L-Lys(Fmoc)-NHboc was dissolved in 75 mLanhydrous CH₂Cl₂, and then deprotected with 50% trifloroacetic acid(TFA, 75 mL) for 1 hr. The CH₂Cl₂ and TFA were then removed undervacuum, 35° C. Then, 1 mL of CH₂Cl₂ and 2 mL of toluene were addedthrice to the residue, and then removed thrice under vacuum, to yield abrown gum residue in quantitative yield.

(iv) BzlO-L-Lac-D-Val-D-Hyisoval-L-Lys(Fmoc)-L-Lac-D-Val-NHboc (LinearDepsi Peptide)

In a round bottom flask 3.73 g (12.89 mmol, 1.15 eq.) ofL-Lac-D-Val-NHboc, (block 3) was dissolved in 200 mL of anhydrousCH₂Cl₂. The solution was stirred for 5 min at room temperature, then6.71 g (1.15 eq.) of PyBOP, 1.97 g (1.15 eq.) of HOBT, and 19.5 mL (10eq.) of DIPEA were added. The solution was stirred for 5 min. where uponthe BzlO-L-Lac-D-Val-D-hyisoval-L-Lys(Fmoc)-NH₂ in anhydrous CH₂Cl₂ wasadded. This solution mixture was then stirred for an additional 18 hrsat room temperature. The insoluble urea thus formed was filtered off,then the solution was washed thrice with 200 mL saturated NaHCO₃, thricewith 200 mL 10% citric acid, once with water and then dried over Na₂SO₄.The CH₂Cl₂ fraction was then removed under vacuum, 45° C. to yield alight brown crystal. The product was purified by column chromatography(CH₂Cl₂:EtOAc:hexane 2:3:5) to yield 5.25 g of a white crystal, yield46.79%. R_(f)=0.40 (CH₂Cl₂:EtOAc:hexane 2:3:5); ¹H-NMR (400 MHz, CDCl₃),δ 0.92-1.05 (m, 18H), 1.20-1.31 (m, 2H), 1.31-1.58 (m, 17H), 1.88-2.10(m, 3H), 2.25-2.43 (m, 2H), 3.04-3.29 (m, 2H), 3.94 (t, J=6.82, 1H),4.17-4.23 (m, 1H), 4.32-4.43 (m, 3H), 4.44-4.50 (m, 1H), 5.03 (d,J=3.54, 1H), 5.10-5.25 (m, 5H), 5.38-5.43 (m, 1NH), 7.26-7.35 (m, 7H),7.39 (t, J=7.58, 2H), 7.51 (d-br, J=8.08, 1NH), 7.58 (d, J=7.58, 2H),7.75 (d, J=7.58, 2H); ¹³C-NMR (100 MHz, CDCl₃), δ 16.8 (CH₃), 16.9(CH₃), 17.4 (CH₃), 18.6 (CH₃), 18.7 (CH₃), 19.0 (CH₃), 19.1 (CH₃), 19.3(CH₃), 23.0 (CH₂), 28.4 (3×CH₃), 29.4 (CH₂), 30.3 (CH), 30.3 (CH), 31.7(CH), 32.0 (CH₂), 40.5 (CH₂), 47.3 (CH), 53.7 (CH), 58.1 (CH), 60.0(CH), 66.7 (CH₂), 67.1 (CH₂), 69.2 (CH), 70.1 (CH), 78.9 (CH), 80.7 (C),120.1, 125.2, 127.1, 127.8, 128.3, 128.4, 128.6 (CH—Ar), 135.4, 141.4,144.1 (C—Ar), 156.4, 156.6, 169.6, 170.4, 170.6, 171.2, 171.4, 171.9(C═O).

(v) L-Lac-D-Val-D-Hyisoval-L-Lys(Fmoc)-L-Lac-D-Val-NHboc

In a round bottom flask, 5.1 g (5.1 mmol) of theBzlO-L-Lac-D-Val-D-hyisoval-L-Lys(Fmoc)-L-Lac-D-Val-NHboc was dissolvedin 100 mL anhydrous CH₂Cl₂. The benzyl ester group was removed byhydrogenation reaction using 0.5 g of Pd activated carbon as thecatalyst, and gas hydrogen (H₂) flowed over for 4 hrs. Then the Pdactivated carbon was filtered off and the solution was concentratedunder vacuum, 45° C., to yield a white crystal. The product was obtainedby column chromatography (CH₂Cl₂:MeOH 80:20) to yield 4.5 g of a whiteamorphous solid, yield 97.0%. R_(f)=0.5 (CH₂Cl₂:MeOH 80:20); ¹H-NMR (400MHz, CD₃OD), δ 0.91-1.07 (m, 12H), 1.36-1.51 (m, 19H), 1.75-1.89 (m,1H), 1.89-2.03 (m, 1H), 2.06-2.31 (m, 3H), 3.05-3.16 (m, 2H), 3.98-4.09(m, 1H), 4.13-4.23 (m, 1H), 4.27-4.35 (m, 1H), 4.36-4.58 (m, 3H), 4.83(d, J=5.56, 1H), 5.01-5.10 (m, 1H), 5.14-5.28 (m, 1H), 7.30 (t, J=7.58,2H), 7.38 (t, J=7.58, 2H), 7.63 (d, J=7.58, 2H), 7.77 (d, J=7.58, 2H);¹³C-NMR (100 MHz, CD₃OD), δ 17.8 (CH₃), 18.4 (CH₃), 19.0 (CH₃), 19.6(CH₃), 20.0 (CH₃), 24.4 (CH₂), 29.2 (3×CH₃), 30.7 (CH₂), 32.1 (CH), 32.2(CH), 32.3 (CH), 32.5 (CH₂), 41.8 (CH₂), 48.9 (CH), 54.3 (CH), 59.5(CH), 61.3 (CH), 68.0 (CH₂), 71.2 (CH), 71.9 (CH), 80.4 (CH), 81.0 (C),121.3, 126.6, 128.6, 129.2 (CH—Ar), 143.0, 145.7 (C—Ar), 158.7, 159.3,172.3, 173.0, 173.3 173.4, 174.5 (C═O).

(vi) Cyclo-L-Lac-D-Val-D-Hyisoval-L-Lys(Fmoc)-L-Lac-D-Val (CyclicDepsi-Peptide)

In a round bottom flask, 1.1 g (1.2 mmol) of theL-Lac-D-Val-D-hyisoval-L-Lys(Fmoc)-L-Lac-D-Val-NHboc was dissolved in 75mL anhydrous CH₂Cl₂, and then deprotected with 50% trifloroacetic acid(TFA, 75 mL) for 1 hr. The CH₂Cl₂ and TFA were then removed undervacuum, 35° C. Then, 1 mL of CH₂Cl₂ and 2 mL of toluene were addedthrice to the residue, and then removed thrice under vacuum, to yieldL-Lac-D-Val-D-hyisoval-L-Lys(Fmoc)-L-Lac-D-Val-NH₂ (a brown gum residue)in quantitative yield.

In a round bottom flaskL-Lac-D-Val-D-hyisoval-L-Lys(Fmoc)-L-Lac-D-Val-NH₂ was dissolved in 500mL of anhydrous DMF. The solution was stirred for 15 min at 0° C., whereupon 2.1 mL (10 eq.) of DIPEA, 0.60 g (1.3 eq.) ofO-(7-Azabenzotriazole-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU), and 0.21 g (1.3 eq.)1-Hydroxy-7-azabenzotriazole (HOAT) were added. The solution wascontinuously stirred at 0° C. for 8 hours, and then it was allowed to bestirred for an additional 1 hour at room temperature. The DMF was thenremoved under vacuum, 45° C. to yield a brown gum. After that, 200 mL ofCH₂Cl₂ was added to precipitate the insoluble urea from the solution.The insoluble compound thus formed was filtered off, then the solutionwas washed thrice with 200 mL saturated NaHCO₃, thrice with 200 mL 10%citric acid, once with water and then dried over Na₂SO₄. The CH₂Cl₂fraction was then removed under vacuum, 45° C. to yield an off-whitecrystal. The product was purified by column chromatography(CH₂Cl₂:EtOAc:hexane 2:4:4) to yield 0.59 g of a white crystal, yield61.65%. R_(f)=0.35 (CH₂Cl₂:EtOAc:hexane 2:4:4); ¹H-NMR (400 MHz, CDCl₃),δ 0.88-1.04 (m, 18H), 1.24-1.41 (m, 4H), 1.41-1.65 (m, 6H), 1.88-2.05(m, 3H), 2.15-2.39 (m, 2H), 3.01-3.37 (m, 2H), 4.10-4.28 (m, 2H),4.28-4.50 (m, 3H), 4.63-4.75 (m, 1H), 5.05-5.25 (m, 3H), 5.25-5.40 (m,1H), 6.64 (d, J=8.59, 1NH), 6.75-6.89 (m, 1NH), 7.13-7.24 (m, 1NH), 7.30(t, J=7.58, 2H), 7.40 (t, J=7.58, 2H), 7.53-7.62 (m, 2H), 7.76 (d,J=7.58, 2H); ¹³C-NMR (100 MHz, CDCl₃), δ 15:5 (CH₃), 17.4 (CH₃), 17.8(CH₃), 18.0 (CH₃), 18.6 (CH₃), 19.0 (CH₃), 19.1 (CH₃), 19.3 (CH₃), 23.1(CH₂), 29.4 (CH₂), 29.6 (CH), 30.1 (CH₂), 30.8 (CH), 31.3 (CH), 40.2(CH₂), 47.4 (CH), 53.4 (CH), 56.7 (CH), 59.6 (CH), 66.7 (CH₂), 69.9(CH), 71.8 (CH), 79.5 (CH), 120.2, 125.1, 127.2, 127.9 (CH—Ar), 141.5,144.1 (C—Ar), 156.8, 169.1, 170.6, 170.7, 171.0, 172.7 (C═O). EIS MS m/zcalcd. for C₄₂H₅₇N₄O₁ (MH⁺) 793.9 found 793.9.

(vii) Cyclo-L-Lac-D-Val-D-Hyisoval-L-Lys(NH₂)-L-Lac-D-Val

In a round bottom flask, 0.8 g (1.01 mmol) ofcyclo-L-Lac-D-Val-D-hyisoval-L-Lys(Fmoc)-L-Lac-D-Val was dissolved in 50mL solution of 10% piperidine in CH₂Cl₂ for 20 min. The CH₂Cl₂ andpiperidine were then removed under vacuum, 35° C. to yield a brown gumresidue. Then, 1 mL of CH₂Cl₂ and 2 mL of toluene were added thrice tothe residue, and removed thrice under vacuum. The product was purifiedby column chromatography (CH₂Cl₂:MeOH 30:1) to yield 0.42 g of off-whitecrystal, yield 72.41%. R_(f)=0.25 (CH₂Cl₂:MeOH 30:1); ¹H-NMR (400 MHz,CDCl₃), δ 0.87-1.04 (m, 18H), 1.23-1.57 (m, 8H), 1.73-1.90 (m, 2H),1.95-2.09 (m, 2H), 2.09-2.19 (m, 1H), 2.19-2.39 (m, 2H), 3.18-3.34 (m,2H), 3.38 (d, J=3.03, 1H), 4.41-4.54 (m, 1H), 4.54-4.70 (m, 2H),5.15-5.38 (m, 2H), 6.92-7.02 (m, 1NH), 7.25-7.32 (m, 1NH), 7.30-7.42 (m,1NH), 7.55-7.74 (m, 1NH); ¹³C-NMR (100 MHz, CDCl₃), δ 15.9 (CH₃), 17.9(CH₃), 18.0 (CH₃), 18.0 (CH₃), 19.1 (CH₃), 19.3 (CH₃), 28.0 (CH₂), 28.9(CH₂), 30.5 (CH), 30.9 (CH), 31.4 (CH₂), 31.9 (CH), 42.1 (CH₂), 52.0(CH), 53.6 (CH), 57.3 (CH), 71.1 (CH), 71.4 (CH), 76.4 (CH), 169.6,170.4, 170.8, 171.2, 174.4, 175.3 (C═O).

(viii) Compound I

In a round bottom flask, 0.40 g (0.70 mmol) ofcyclo-L-Lac-D-Val-D-hyisoval-L-Lys(NH₂)-L-Lac-D-Val was dissolved in 20mL of anhydrous CH₂Cl₂. The solution was stirred for 10 min at 0° C.,then 0.1446 g (1 eq.) of 1,3-dicyclohexylcarbodiimide (DCC) was addedfollowed by adding 0.0086 g (0.1 eq.) DMAP. The solution was stirred for10 min. in ice bath where upon 0.1611 g (1 eq.) of 11-mercaptoundecanoicacid was added. After the solution was stirred at 0° C. for 1 hr, it wasthen stirred for an additional 23 hrs. at room temperature. Theinsoluble urea thus formed was filtered off, then the CH₂Cl₂ was removedunder vacuum, 45° C. to yield an off-white gum. The product was obtainedby column chromatography (CH₂Cl₂:MeOH 60:1) to yield 0.38 g of anoff-white oil, yield 70.37%. R_(f)=0.21 (CH₂Cl₂:MeOH 60:1); ¹H-NMR (400MHz, CDCl₃), δ 0.77 (d, J=7.07, 3H), 0.92 (d, J=7.07, 3H), 0.93-1.05 (m,12H), 1.21-1.42 (m, 20H), 1.45-1.57 (m, 8H), 1.57-1.72 (m, 6H),1.75-1.98 (m, 2H), 1.98-2.16 (m, 2H), 2.16-2.36 (m, 3H), 2.44 (t,J=7.58, 2H), 2.52 (q, J=7.33, 2H), 3.18-3.33 (m, 2H), 4.41-4.51 (m, 1H),4.67-4.77 (m, 1H), 4.78-4.85 (m, 1H), 4.92 (d, J=5.31, 1H), 5.18-5.31(m, 2H), 6.92 (d, J=8.59, 1NH), 7.08-7.15 (m, 1NH), 7.25 (d, J=9.09,1NH), 7.60 (d, J=6.06, 1NH); ¹³C-NMR (100 MHz, CDCl₃), δ 17.5 (CH₃),17.9 (CH₃), 18.0 (CH₃), 18.8 (CH₃), 19.1 (CH₃), 19.2 (CH₃), 25.1 (CH₂),25.7 (CH₂), 25.8 (CH₂), 28.0 (CH₂), 28.9 (CH₂), 29.1 (CH₂), 29.2 (CH₂),29.6 (CH₂), 30.4 (CH), 30.6 (CH), 31.5 (CH), 34.1 (CH₂), 34.3 (CH₂),42.1 (CH₂), 51.7 (CH), 56.6 (CH), 57.1 (CH), 71.3 (CH), 71.5 (CH), 78.1(CH), 169.6, 169.7, 169.9, 170.5, 170.9, 173.0, 175.3 (C═O). EIS MS m/zcalcd. for C₃₈H₆₆N₄O₁₀S (M⁺) 771.0 found 771.8.

Example 2 Preparation and Characterization of SAMs

Gold slides were purchased from Evaporated Metal Films (EMF, Ithaca,N.Y.). The slides have dimensions of 25 mm×75 mm×1 mm with cut edges,fabricated on a float glass substrate, coated with 50 Å of chromiumfollowed by 100 Å of gold. The substrates were cut in different sizesdepending to the experimental needs. The slides were cleaned in piranhasolution (70% concentrated sulfuric acid and 30% hydrogen peroxide) for15 minutes, rinsed with water and ethanol, and dried with nitrogenbefore use. SAMs of the compound I were prepared by immersing a cleangold slide into a 1-3 mM solution of the thiol in ethanol for up to 48hours. The SAMs were rinsed with ethanol and dried with nitrogen gasbefore use.

Contact angle measurements were obtained with a Rame-Hart Model 100-00Goniometer. Drops of water (1 μL) were deposited with a micropipette andthe sessile drop contact angle was measured. The average of at leastthree measurements from three different samples was obtained.

Thickness measurements were determined with a manual photoelectricRudolf 439L633P ellipsometer (Rudolph Instruments, Fairfield N.J.). Thechange in polarization state of light reflected from the surface wasmeasured at 70° angle of incidence using a HeNe laser (632.8 nm) as thesource. The thickness of the film was calculated, using themanufacturers software, assuming values for the extinction coefficientand refractive index of the samples to be 0 and 1.47, respectively. Thevalues reported here are the average values obtained from at least threedifferent samples.

IR spectra were obtained with a Nexus FT-IR spectrometer equipped with aThermoNicolet grazing angle accessory and a liquid-nitrogen cooled MCTAdetector. The IR beam was incident at 75 degree on the gold substrates.The optical path was purged with nitrogen gas before and during dataacquisition. IR spectra were obtained by collecting 64 scans, with a 4cm⁻¹ resolution, from 4000 to 800 cm⁻¹. A clean gold substrate was usedas a background before the acquisition of each spectrum.

Impedance measurements were performed with the same three-electrodesetup used for cyclic voltammetry. A 1255-HF frequency response analyzerwas used in combination with the EG&G Princeton Applied ResearchPotentiostat/Galvanostat. Impedance measurements were collected with abackground electrolyte solution of 0.1 M tetraethylammonium chloride andtitrated with 0.1 M solutions of metal chlorides (MCl, M=Na⁺, K⁺, Li⁺,NH₄ ⁺). The electrolyte solution was bubbled with nitrogen at least 5minutes before data acquisition. During the measurements, a constantflow of nitrogen was maintained. The impedance plots were obtained in afrequency range of 10 kHz to 0.1 Hz, at an applied dc voltage of −0.5 Vvs Ag/AgCl, with an AC amplitude of 5 mV. At least twenty-five (25)frequencies were used for each measurement and the impedance data wasfitted to an equivalent circuit using the LEVMRUN software package forcomplex non-linear least square calculations. (See, Macdonald, R., CNLSImmitance, Inversion, and Simulation Fitting Programs for Windows andMS-DOS LEVM Manual 8.0, University of North Carolina: Chapel Hill, N.C.(2003), the entire teaching of which is incorporated herein byreference.)

Molecular modeling was preformed on a Dell Precision PWS 670 runningWindows XP using the Molecular Operating Environment (MOE) version2004.03 package (Chemical Computing Group Inc., Montreal, Quebec,Canada). The energy minimized structure of a target compound wascalculated using two different force fields for comparative purposes,namely, AMBER94 and MMFF94. Calculations with each force field werecarried out with a dielectric of 80 (aqueous environment). Before eachconformation calculation the partial charges on the molecule werecalculated using the corresponding force field. A stochasticconformational search for the equilibrium geometry followed by adynamics simulation using the NVT (constant particle number N, constantvolume V and constant temperature T) statistical ensemble. The dynamicssimulation was performed for 20 ps, heating the structure to 400 K,equilibrated at 310 K and cooled to 290 K in the dynamics thermal cycleat a rate of 10 K/ps. The lowest energy structure obtained from thesedynamics calculations was then minimized again. For all the calculationsperformed, the dynamic simulation resulted in a geometry that was eitherequal to, or lower in energy than the result obtained from thestochastic search. Host—guest calculations were performed by introducingan ion into the centre of the host structure. These systems wereminimized, a dynamic simulation was performed and then the resultminimized again as previously described. A stochastic conformationalsearch was not carried out for the host guest systems since the randomstarting coordinates generally places the ion at distance beyond theinfluence of the host molecules.

Although the invention has been described with respect to variousembodiments, it should be realized that this invention is also capableof a wide variety of further and other embodiments according to thescope and the breadth of the claims.

1. A compound of Formula (I)


2. A process of making the compound of claim 1 comprising: (1) a stepfor converting the compound of Formula (A)

into the compound of Formula (B)

and (2) a step for coupling the compound of Formula (B) with11-mercaptoundecanoic acid to yield the compound of claim
 1. 3. Theprocess of claim 2 further comprising a step for converting the compoundof Formula (C)

into the compound of Formula (A)


4. The process of claim 3 further comprising the step for removing thet-Butyloxycarbonyl group from the compound of Formula (D)


5. The process of claim 4 further comprising a step for converting thecompound of Formula (E)

into the compound of Formula (D)


6. The process of claim 5 further comprising the step for coupling thecompound of formula (F)

with the compound of Formula (G)


7. The process of claim 6 further comprising the step for removing thet-Butyloxycarbonyl group from the compound of Formula (H)


8. The process of claim 7 further comprising the step for coupling thecompound of Formula (J)

with the compound of Formula (K)


9. The process of claim 8 further comprising the step for removing thet-Butyloxycarbonyl group from the compound of Formula (L)


10. The process of claim 9 further comprising the step for convertingthe compound of Formula (M)

into the compound of formula (K)


11. The process of claim 10 further comprising the step for coupling(R)-benzyl 2-hydroxy-3-methylbutanoate with the compound of Formula (N)


12. The process of claim 11 further comprising the step for coupling(R)-2-hydroxy-3-methylbutanoic acid with phenylmethanol.
 13. The processof claim 12 further comprising the step for converting the compound ofFormula (L)

into the compound of Formula (O)


14. The process of claim 13 further comprising the step for coupling(S)-benzyl 2-hydroxypropanoate with(R)-2-(tert-butoxycarbonylamino)-3-methylbutanoic acid.
 15. The processof claim 14 further comprising the step for coupling(S)-2-hydroxypropanoic acid with phenylmethanol.
 16. A sensor comprisinga self assembled monolayer of the compound of claim 1 on gold means forsupporting said monolayer.
 17. A method of making the sensor of claim 16comprising: a step for selecting gold means of appropriate size forsupporting the monolayer; and a step for immersing said gold means in asolution of the compound of claim 1, wherein a self assembled monolayerof said compound forms on said gold means.